ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 427 of the CYP21A2 protein (p.Arg427His). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individual(s) with classic salt-wasting and/or simple virilizing congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 11600539, 30995443). It has also been observed to segregate with disease in related individuals. This variant is also known as R426H. ClinVar contains an entry for this variant (Variation ID: 12175). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP21A2 protein function. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 11600539). This variant disrupts the p.Arg427 amino acid residue in CYP21A2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12213891, 18381579, 30995443). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.